1N5O

Structural consequences of a cancer-causing BRCA1-BRCT missense mutation

Summary for 1N5O

• Entry DOI: 10.2210/pdb1n5o/pdb
• Related: 1jnx
• Descriptor: Breast cancer type 1 susceptibility protein, COBALT (II) ION, SULFATE ION, ... (4 entities in total)
• Functional Keywords: brca1, brct, missense mutation, protein folding, breast cancer, antitumor protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 24808.29

Authors

Williams, R.S.,Glover, J.N.M. (deposition date: 2002-11-06, release date: 2002-12-25, Last modification date: 2024-02-14)

Primary citation

Williams, R.S.,Glover, J.N.M.
Structural consequences of a cancer-causing BRCA1-BRCT missense mutation
J.Biol.Chem., 278:2630-2635, 2003

PubMed Abstract: The integrity of the carboxyl-terminal BRCT repeat region is critical for BRCA1 tumor suppressor function; however, the molecular details of how a number of clinically derived BRCT missense mutations affect BRCA1 function remain largely unknown. Here we assess the structural response of the BRCT tandem repeat domain to a well characterized, cancer-associated single amino acid substitution, Met-1775 --> Arg-1775. The structure of BRCT-M1775R reveals that the mutated side chain is extruded from the protein hydrophobic core, thereby altering the protein surface. Charge-charge repulsion, rearrangement of the hydrophobic core, and disruption of the native hydrogen bonding network at the interface between the two BRCT repeats contribute to the conformational instability of BRCT-M1775R. Destabilization and global unfolding of the mutated BRCT domain at physiological temperatures explain the pleiotropic molecular and genetic defects associated with the BRCA1-M1775R protein.

PubMed: 12427738
DOI: 10.1074/jbc.M210019200

Experimental method

X-RAY DIFFRACTION (2.8 Å)